Severe chronic hepatitis has been increasingly recognized among hemophiliacs since the introduction of commercial factor VIII and IX concentrates. This disease is most likely related to persistent infection with non-A, non-B (NANB) hepatitis virus(es), hepatitis B virus (HBV), or hepatitis delta virus (HDV), a defective RNA virus which is dependent upon coinfection with HBV for essential helper functions. HDV is recognized to be associated with more serious manifestations of chronic liver disease in HBV carriers, but the relative contribution of NANB, HBV and HDV viruses to the development of chronic liver disease in hemophiliacs is uncertain. We propose to elucidate the role of HDV in the development of chronic liver disease in hemophiliacs. A large population of patients with hemophilia (n=1100) from seven hemophilia centers will be screened for HBV and HDV serological markers. Five cohorts will be established: those with coexistent HBV and HDV infection (n=50), HBV infection alone (n=50), previous HBV infection (n=100, age and study center-matched for groups A and B), and those with no markers of HBV (n=100, to be immunized against HBV). Data concerning hepatitis risk factors, including previous transfusion therapy, would be collected and noninvasive assessments of liver function would be made. Since available tests for HDV infection have limited sensitivity and are not necessarily specific for HDV persistence, HDV RNA would be detected in serum by molecular hybridization using cloned HDV cDNA and single-stranded RNA probes. Western blot analysis would be used to assess antibody responses to HDV. A multifactorial analysis of clinical and virological data would be conducted at the end of the first year of study. Patients would be reevaluated clinically and virologically at six month intervals to ascertain risk factors for acquisition of HBV and HDV infections, and assess the prevalence and rate of progression of liver disease in each group.